Discovery and Optimization of Novel Pyridines as Highly Potent and Selective Glycogen Synthase Kinase 3 Inhibitors

The study focused on developing novel pyridine derivatives as potent and selective inhibitors of glycogen synthase kinase-3 (GSK3), a key enzyme involved in energy regulation and a target for treating non-insulin dependent diabetes mellitus. The synthesized compounds demonstrated low nanomolar potency and high selectivity, overcoming challenges posed by the enzyme's similarity to other kinases like CDC2. These inhibitors effectively activated glycogen synthase in insulin receptor-expressing cells and primary rat hepatocytes, with suitable pharmacokinetic and pharmacodynamic profiles for oral administration. The X-ray co-crystal structure of GSK3-beta with one of the compounds provided insights into the structural features contributing to their efficacy.